ONCOGENESIS Bcl-2 Attenuates Mismatch Repair

Youn et al. uncovered a pathway whereby Bcl-2 inhibits DNA mismatch repair by attenuating E2F activity, providing a novel mechanism for its role in oncogenesis. Bcl-2 overexpression has been implicated in the pathogenesis of follicular lymphoma and other forms of cancer, an effect that is often ascribed to its role in inhibiting apoptosis (see La Thangue). Using a human fibroblast cell line in which Bcl-2 expression was regulated through exposure to ponasterone A, Youn et al. showed that Bcl-2 overexpression enhanced spontaneous mutagenesis and mutagenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and reduced mRNA and protein expression of the mismatch repair protein MSH2. Mismatch repair activity was reduced in nuclear extracts of Bcl-2-expressing cells. Mutational analysis indicated that the effects of Bcl-2 on mismatch repair were independent of its antiapoptotic effect. Bcl-2 promoted accumulation of hypophosphorylated retinoblastoma tumor-suppressor protein (Rb, which binds and inactivates the transcription factor E2F1) and association of E2F1 with pRb. Moreover, chromatin immunoprecipitation analysis revealed that Bcl-2 suppressed E2F association with the MSH2. Human B cell lymphoma cell lines that overexpressed Bcl-2 showed reduced expression of MSH2 and decreased mismatch repair compared with those in a line with little Bcl-2 expression. The Bcl-2-expression cells had enhanced sensitivity to MNNG-induced mutagenesis and reduced activity of E2F. Finally, the authors used immunoprecipitation to show that Bcl-2 associated with Cdk2 (which phosphorylates Rb) and reduced Cdk2's in vitro kinase activity. Thus, the authors propose that the mutagenic effects of Bcl-2 are mediated through suppression of mismatch repair, by way of E2F inhibition by hypophosphorylated Rb.

C.-K. Youn, H.-Y. Cho, S.-H. Kim, H.-B. Kim, M.-H. Kim, I.-Y. Chang, J.-S. Lee, M.-Y. Chung, K.-S. Hahm, H. J. You, Bcl-2 expression suppresses mismatch repair activity through inhibition of E2F transcriptional activity. Nat. Cell Biol. 7, 137-147 (2005). [PubMed]

N. B. La Thangue. A mismatched role for Bcl-2. Nat. Cell Biol. 7, 101-102 (2005). [PubMed]